bims-nakice 2026-08-09 papers

Issue of 2026–08–09
seven papers selected by
Santosh Phuyal, Oslo Universitetssykehus

Cancer Immunol Immunother. 2026 Aug 04. pii: 198. [Epub ahead of print]75(8):

The CREM-IL-15 axis: decoding the persistence-exhaustion paradox in NK cell immunotherapy.

Amr Ali Mohamed Abdelgawwad El-Sehrawy, Mutaz Jamal Al-Khreisat, Jalpa R Patel, Makhfirat Kibriyeva, Lutfullayeva Gulnoza, Khayriddin Qosimov, Lhyb Mohammed Abdul, Navin Kumar Tailor.

Natural killer (NK) cells are critical components of the innate immune system, renowned for their ability to recognize and eliminate malignant and infected cells without prior sensitization. NK cell immunotherapy encompasses various approaches, including adoptive transfer of ex vivo expanded NK cells, cytokine stimulation to enhance their activity, and genetic modifications to improve persistence and specificity. CREM is a cAMP-responsive transcription factor that modulates gene expression in response to receptor- and cytokine-driven signaling. Recent evidence now shows that IL-15 and CAR stimulation rapidly induce CREM in activated NK cells. Rafei (Nature 643:1076-1086, 2025) further demonstrated in CAR-NK models that CREM functions as a regulatory checkpoint limiting NK cell cytotoxicity and cytokine production, while its relevance in resting/native NK cells remains to be established. The CREM-IL-15 signaling axis has emerged as a pivotal regulator of NK cell biology, influencing their development, activation, and longevity. IL-15 is a critical cytokine for NK cell survival, proliferation, and functional maturation. Understanding this axis is vital, as it offers insights into mechanisms that sustain NK cell activity and those that lead to functional exhaustion, thereby informing strategies to enhance therapeutic efficacy. A central challenge in NK cell immunotherapy is balancing cellular persistence with functional exhaustion. Persistent NK cell activity is desirable for sustained tumor control; however, prolonged activation often results in cellular exhaustion characterized by diminished cytotoxicity and cytokine production. This paradox hampers the long-term success of NK cell-based treatments. The CREM-IL-15 axis plays a complex role in this dynamic, potentially promoting NK cell survival and persistence while also contributing to exhaustion under certain conditions. Deciphering the molecular underpinnings of this paradox is essential for developing interventions that maintain NK cell functionality over time, thereby improving therapeutic outcomes in cancer patients.

Keywords: CREM; Cancer; Cytokine; IL-15; Immunotherapy; NK cell

DOI: https://doi.org/10.1007/s00262-026-04506-9

Mol Ther Adv. 2026 Sep 10. 34(3): 201813

Natural killer cell cryopreservation: Influence of composition, temperature, and granules on post-thaw survival and function.

Adam Joules, Troy Louwagie, Akshat S Mallya, Allison Hubel.

Natural killer (NK) cells are promising off-the-shelf cancer immunotherapies, but their scalable deployment requires effective cryopreservation. Conventional dimethyl sulfoxide (DMSO)-based methods are associated with toxicity and persistent post-thaw functional impairment, and the mechanisms underlying NK cell cryoinjury remain incompletely understood. We investigated NK cell dysfunction following cryopreservation and evaluated DMSO-free cryoprotectant formulations as alternative strategies. DMSO-free formulations were optimized using a differential evolution algorithm. Cryopreserved NK-92 cells were assessed post-thaw for viability, recovery, proliferation, and cytotoxicity over 5 days. Raman cryomicroscopy and flow cytometry were used to characterize cytolytic granule localization and integrity during cooling and freezing. Pre-freezing chemical degranulation was performed to probe granule-mediated injury. Both DMSO-based and DMSO-free formulations had immediate post-thaw recovery and viability over 80% but had notable cell loss over 24 h. Although proliferation resumed by 48 h, expansion remained attenuated, and cytotoxic function was reduced by ≥ 20% and did not recover after 3-5 days. Imaging revealed temperature- and cryoprotective agent (CPA)-induced granule redistribution and destabilization. Pre-freeze degranulation improved short-term recovery and proliferation. These findings support cytolytic granule redistribution and destabilization as contributors to persistent NK cell dysfunction and may inform future cryopreservation strategies for NK cell therapies.

Keywords: DMSO-free; Raman; cell therapy; cryopreservation; differential evolution; natural killer

DOI: https://doi.org/10.1016/j.omta.2026.201813

STAR Protoc. 2026 Aug 04. pii: S2666-1667(26)00412-0. [Epub ahead of print]7(3): 104759

Protocol for conditional mapping of proximal interactomes of dimeric protein complexes using a BioID-based complementation approach.

Abishankari Rajkumar, Antoine Gaudreau-Lapierre, Curtis L F Anthony, Laura Trinkle-Mulcahy.

Here, we provide a protocol for conditional mapping of proximal interactomes of dimeric protein complexes using a BioID-based complementation approach. We describe steps for fusing amino- and carboxyl-terminal fragments of the biotin ligase TurboID to proteins known to interact within cells. This interaction drives re-formation of an active ligase and biotinylation of nearby proteins. We then detail procedures for capturing biotinylated proteins on a streptavidin affinity matrix for identification by mass spectrometry and Python-based scripts for identifying high-confidence proximal interactors. For complete details on the use and execution of this protocol, please refer to Rajkumar et al.1.

Keywords: Cell Biology; Cell-based Assays; Proteomics

DOI: https://doi.org/10.1016/j.xpro.2026.104759

Acta Biomater. 2026 Aug 02. pii: S1742-7061(26)00524-6. [Epub ahead of print]

Hydrophilic porphyrin copolymers combined with autophagy inhibitors enhance tumor photothermal/photodynamic therapy.

Yadong Liu, Yifan Xue, Hongru Lin, Junjie Tang, Han Yang, Dan Peng, Dalin Wu, Jie Liu.

Synergistic photodynamic and photothermal therapy (PDT/PTT) holds immense promise for cancer treatment, yet its efficacy is often compromised by limited photosensitizer performance, glutathione (GSH)-mediated ROS quenching, and tumor-protective autophagy. Herein, we developed a GSH-responsive hydrophilic porphyrin copolymer (PPS) that covalently integrates porphyrin into the polymer backbone, ensuring high loading capacity and minimal carrier-related toxicity. PPS exhibits robust absorption around 800 nm, enabling simultaneous PDT and PTT under a single NIR laser. By incorporating the autophagy inhibitor chloroquine (CQ), the resulting CQ@DPPS nanosystem achieves multi-modal synergy: intracellularly, CQ not only inhibits phototherapy-induced autophagic flux to suppress cell survival but also facilitates the lysosomal escape of photosensitizers, heightening programmed cell death via Bcl-2 inhibition and Caspase-3 activation. Crucially, CQ@DPPS significantly activates NK cell-mediated innate immune surveillance and enhances the secretion of granzyme B (GZMB) in NK cells by downregulating MHC-I expression on the surface of tumor cells. In vivo, CQ@DPPS combined with 808 nm irradiation achieved complete tumor regression in HCT116-bearing mice and significantly attenuated hepatic metastasis. This work provides a potent strategy to overcome phototherapy resistance through the integration of autophagy inhibition, dual-mode phototherapy, and innate immune activation. STATEMENT OF SIGNIFICANCE: Clinical translation of PDT/PTT therapy is hindered by inefficient photosensitizer delivery, GSH-mediated ROS depletion, and cytoprotective autophagy in tumors. Here, we report a GSH-responsive hydrophilic porphyrin copolymer with porphyrin covalently integrated into the polymer backbone, enabling high loading, reduced carrier burden, and effective 808 nm-triggered PDT/PTT. Co-delivery of CQ in the CQ@DPPS nanosystem not only suppresses protective autophagic flux, but also promotes lysosomal escape, mitochondrial apoptosis, and NK cell-mediated antitumor immunity through reduced MHC-I expression and increased GZMB secretion. This multi-mechanistic platform achieved complete tumor regression and reduced hepatic metastasis in vivo, offering a promising biomaterial strategy to overcome major barriers in phototherapy and facilitate clinical translation.

Keywords: Autophagy; Hydrophilic porphyrin; Photodynamic therapy; Photothermal therapy; Polymer

DOI: https://doi.org/10.1016/j.actbio.2026.08.001

Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2619024123

How small can a cell be?

Shicong Xie, Jan M Skotheim.

DOI: https://doi.org/10.1073/pnas.2619024123

STAR Protoc. 2026 Aug 05. pii: S2666-1667(26)00396-5. [Epub ahead of print]7(3): 104743

Protocol for detecting protein recruitment to clathrin structures in cultured cells.

Laura A Orofiamma, Costin N Antonescu.

Clathrin-mediated endocytosis internalizes key cell-surface receptors and relies on coordinated recruitment of adaptors and accessory proteins to clathrin structures. Here, we present a protocol for quantifying protein recruitment to diffraction-limited clathrin structures at the plasma membrane. We describe steps for the inducible expression of tagged proteins, total internal reflection fluorescence (TIRF) microscopy, the analysis of proteins within clathrin structures, UltraID-based proximity-labeling, and western blotting detection of proteins in clathrin structures. This protocol is applicable to the detection of any protein within clathrin or related structures. For complete details on the use and execution of this protocol, please refer to Orofiamma et al.1.

Keywords: Cell Membrane; Cell culture; Cell-based Assays; Microscopy

DOI: https://doi.org/10.1016/j.xpro.2026.104743